R01 Slowing aging by multiplexing (SLAM) Project Summary/Abstract Aging is a complex multifactorial process, meaning that multiple pathways need to be targeted to effectively slow aging. A number of molecular targets are well known for influencing aging, but only a few have been successfully targeted with individual drugs, and these drugs do not individually target all aging pathways. Combinations of these drugs would have the potential of effectively broadening the scope of aging targets, but drug combinations have yet to be multiplexed and tested in any meaningful way. Historically, testing single drugs in mouse lifespan studies has provided useful information, but it is costly and time consuming. More importantly, lifespan studies are difficult to recapitulate in humans, making translation of the pre-clinical information challenging. And especially relevant to this proposal, lifespan studies in mice are not well-suited to testing drug combinations that could more effectively target multiple factors involved in aging. We have developed a new paradigm, designated as the Geropathology Grading Platform (GGP), which measures biological age and predicts anti-aging drug responses. We propose to use the GGP to test multiplex combinations of three established anti-aging drugs, rapamycin, acarbose, and ss31 peptide, each affecting different molecular targets but with complementary actions to enhance overall anti-aging effects in mice. This proposal is novel in that it will be the first to test drug multiplexing for preclinical aging studies using biological aging-responsive endpoints.